Method of treating fibrosis

ABSTRACT

The present specification provides methods and compositions for treating fibrosis, particularly pulmonary fibrosis. The pulmonary fibrosis may be idiopathic or arise following an infection of the lung. The lung infection can be by SARS-CoV-2. Lung function stabilizes or is improved as a result of treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S.Provisional Patent Application 63/091,128, filed Oct. 13, 2020, theentire contents of which are incorporated by reference herein.

BACKGROUND

The treatment of fibrotic diseases has proved challenging. Althoughthere are approved drugs of the treatment of some fibrotic diseases,such as pirfenidone and nintedanib for idiopathic pulmonary fibrosis(IPF). However, these drugs only modestly slow progression of thedisease, but do not stop or reverse it. The Hedgehog/GLI signalingpathway is an important regulator of normal embryonic development andhad been implicated in the development of fibrosis as well. However,inhibition of the canonical Hh signaling pathway, for example byinhibiting Smoothened (SMO), a G protein-couple receptor in the Hedgehog(Hh) signaling pathway, has failed to lead to a clinically viabletreatment for pulmonary fibrosis, kidney fibrosis, or myelofibrosis.Indeed, cyclopamine and IPI-926, inhibitors of SMO have been found to beineffective in treating kidney fibrosis. Additionally, a phase 2clinical trial of IPI-926 in myelofibrosis did not support continueddevelopment. A phase 1 b clinical trial of another SMO inhibitor,vismodegib (in combination with pirfenidone) for the treatment of IPFsuggested some degree of efficacy, but many patients dropped out of thestudy because they could not tolerate the drug and development of thedrug for this indication was abandoned.

SUMMARY

Disclosed herein are methods and compositions for treating fibroticdisease using inhibitors of the hedgehog signaling pathway that aresufficiently potent and tolerable to admit of clinical utilization.

One aspect is a method of treating fibrosis comprising administering aninhibitor of Gli1. Inhibition of Gli1 can be indirect. In someembodiments, an inhibitor of SMO is used to indirectly inhibit Gli1.

One aspect is a method of treating fibrosis comprising administeringmeans for inhibiting Gli1. Inhibition of Gli1 can be indirect. In someembodiments, means for inhibiting SMO are used to indirectly inhibitGli1. In various embodiments, one or another genus or species of SMOinhibitor is specifically excluded.

With respect to the above aspects, in some embodiments, the inhibitor ofGli1 or the means for inhibiting Gli1 is an inhibitor of SMO (or meansfor inhibiting SMO). In some embodiments, the inhibitor of SMO, theinhibitor of Gli1, or the means for inhibiting Gli1 or SMO is a compoundof Formula I:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof.Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a methylsulfonyl substituent is equivalent to CH₃—SO₂—. Insome embodiments, the compound of Formula I is4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-yl)phthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethypenzamide(CAS 1258861-20-9):

also known as taladegib.

With respect to the above aspects, in some embodiments, the inhibitor ofSMO, the inhibitor of Gli1, or the means for inhibiting Gli1 or SMO is acompound of Formula II:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound of Formula II is compound L-4, having thestructure

With respect to the above aspects, in some embodiments, the inhibitor ofGli1 or the means for inhibiting Gli1 is administered to a patient inneed thereof, that is, a patient having a fibrotic disease. In someembodiments, the fibrotic disease is idiopathic pulmonary fibrosis(IPF). In some embodiments, the fibrotic disease is pulmonary fibrosisfollowing infection, including a bacterial or viral infection. In mostinstances, the fibrosis develops after years-long chronic infections sothat the role of the infection in causing the fibrosis cannot beconclusively demonstrated; such fibrosis is therefore still classifiedas idiopathic. Covid-19 provides a counterpoint, in that onset offibrosis can be very rapid. In some embodiments, the pulmonary fibrosisfollows infection with SARS-CoV-2. In some embodiments, the fibroticdisease is scleroderma. In some instances, the fibrotic disease issystemic scleroderma (also known as systemic sclerosis) and in furtherinstances, systemic scleroderma involving the lung. In some embodiments,the fibrotic disease is liver fibrosis, such as in non-alcoholicsteatohepatitis (NASH). In some embodiments, the fibrotic disease iskidney fibrosis. In some embodiments, the fibrotic disease is gastricfibrosis. In some embodiments, the patient is a human.

With respect to the above aspects, in some embodiments, the inhibitor ofGli1 or the means for inhibiting Gli1 is administered in an effectiveamount. In some embodiments, the effective amount is effective forreducing symptoms. In some embodiments, the effective amount iseffective for slowing or halting progression of the disease. In someembodiments, the effective amount is effective for reducing impairmentdue to the disease. In some embodiments, the effective amount iseffective for reversing impairment due to the disease (causingimprovement). With respect to IPF, impairment can be measured as changesin lung function, for example, as determined by spirometry. Spirometrymeasures that can be used include forced vital capacity (FVC), forcedexpiratory volume in 1 second (FEV₁), and diffusion capacity of thelungs for carbon monoxide (DL_(CO)). The extent of fibrosis can also beassessed by imaging, such as high resolution computed tomography (HRCT).In some embodiments, the effective amount comprises 50-200 mg of theinhibitor of Gli1 or the means for inhibiting Gli1.

One aspect is a pharmaceutical compound comprising the inhibitor of Gli1or the means for inhibiting Gli1. In some embodiments, the inhibitor ofGli1 or the means for inhibiting Gli1 is a compound of Formula 1 or apharmaceutically acceptable salt thereof. In some embodiment thecompound of Formula 1 is taladegib.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 depicts a comparison of clinical trial results for four IPFtreatments: pirfenidone, nintedanib, GLPG1690, and the Hh inhibitor,vismodegib. The trials for pirfenidone, nintedanib, GLPG1690 wereplacebo controlled, while the vismodegib trial was open label. Thepirfenidone data is the mean of three phase 3 studies at 24 weeks. Thenintedanib data is the mean of two phase 3 studies at 24 weeks. TheGLPG1690 data is phase 1 b data at 12 weeks. The Hh inhibitor(vismodegib) data is phase 1 b data as 24 weeks.

FIG. 2 depicts Gli1 mRNA inhibition (%) in skin samples from patientsreceiving various doses of taladegib.

FIG. 3 depicts the rate of drug-related discontinuations in clinicaltrials for four drugs considered for IPF treatment.

FIGS. 4A-B portray α-SMA protein levels with and without taladegibtreatment in a bleomycin-induced pulmonary fibrosis model. FIG. 4Apresents representative images of anti-α-SMA immunostained lung sectionsfrom sham control, vehicle-treated, and taldegib-treated mice. FIG. 4Bdepicts the percent α-SMA positive area from the individual mice and themean and standard deviation for the treatment groups.

DESCRIPTION

The general mechanism of fibrotic disease has been understood to involvean initial tissue insult causing an upregulation of hedgehog, drivingtransdifferentiation of cells into myofibroblasts (that is, theconversion of differentiated cells (non-stem cells) into another type ofdifferentiated cell, in this case myofibroblasts). The physiologicfunction of myofibroblasts is to repair tissue by depositingextracellular matrix and contracting tissue, as in wound closing.Fibrotic diseases, including IPF, arise from dysregulated woundremodeling involving chronic matrix deposition and tissue contractionlong after initial tissue trauma has been resolved. The herein disclosedmethods and compositions treat fibrotic disease by inhibiting the Hhsignaling pathway so that upregulated hedgehog can no longer drive thispathology, blocking the generation of myofibroblasts and stopping thechronic remodeling that causes fibrosis. Although this mechanism hasbeen clinically validated, the promise of Hh pathway inhibitors to treatfibrosis has so far not been realized.

It is disclosed herein that certain 1,4-disubstituted phthalizines thatare potent inhibitors of SMO and the downstream transcription factorsGli1 and Gli2, and that exhibit a desirable toxicology profile, fulfillthis promise. The present embodiments provide methods of treatment usingcompounds of Formula I:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof.Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a methylsulfonyl substituent is equivalent to CH₃—SO₂—.“Pharmaceutically acceptable salts” refers to the relatively non-toxic,inorganic and organic salts of compounds of the present invention.

Compounds of Formula I and their synthesis are described in U.S. Pat.No. 9,000,023, which is hereby incorporated by reference in itsentirety.

The present embodiments also provide a pharmaceutical compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt thereof, in combination with a pharmaceutically acceptableexcipient, carrier or diluent for use in the methods of treatment. A“pharmaceutically acceptable carrier, diluent, or excipient” is a mediumgenerally accepted in the art for the delivery of biologically activeagents to mammals, e.g., humans.

A paradigmatic compound of Formula I is4-Fluoro-N-methyl-N-(1-(4-(1-methyl-1H-pyrazol-5-Aphthalazin-1-yl)piperidin-4-yl)-2-(trifluoromethypenzamide(CAS 1258861-20-9):

also known as taladegib. Taladegib (also referred to as LY2940680) is apotent, selective, and orally available Smo inhibitor with a favorablesafety profile, capable of disrupting the Hh pathway. This molecule hasbeen in over 192 human subjects and developed initially with theintention of treating oncologic indications with a focus on lung cancerand basal cell carcinoma (BCC). Although primarily cancer patients,these studies allowed for a preliminary understanding of dose andtolerability. Taladegib is orally bioavailable. In some embodiments, themean oral bioavailability is from about 72% to about 91%.

The major metabolite of taladegib, M75, an oxidative N-desmethylationproduct, retains activity as an inhibitor of SMO. M75 is understood tohave lost the methyl group at R² of Formula I, so that position ishydrogen instead of methyl.

Taladegib is well-suited to target the lung compared to vismodegib. Inanimal models, taladegib is greater than 20-fold more potent thanvismodegib at inhibiting Gli1 in the lungs, a downstream effectormolecule that is expressed when the Hh pathway is activated. Theclinically established MTD for taladegib is 400 mg. At this dose, Gli1mRNA inhibition is >85% in skin with a discontinuation of approximately9%. Taladegib has been evaluated clinically at a dose as low as 50 mg(i.e., 8-fold lower than the clinically established MTD) whereinhibition of Gli1 mRNA was still greater than 80%. In contrast,vismodegib inhibits Gli1 mRNA less than 50% at its MTD of 150 mg.Taladegib has a better clinical safety profile than vismodegib, withsubstantially lower occurrence of muscle spasms (40% versus up to 80%).Thus, while vismodegib proved unsuitable for IPF, clinical studies withvismodegib indicated inhibition of the Hh pathway can improve lungfunction in IPF patients.

Compounds of Formula I inhibit Gli1 activity, generally with an IC₅₀ of<40 nM, as measured in Daoy cells and described in U.S. Pat. No.9,000,023. Taladegib has an IC₅₀ of about 2.4 nM in this assay. Suchcompounds constitute means for inhibiting Gli1 activity or means forinhibiting SMO.

Additionally, U.S. Patent Application Publication No. 20200000784 A1 isincorporated herein by reference for all that it teaches about the useof taladegib for the treatment of fibrosis, particularly idiopathicpulmonary fibrosis.

Certain analogues of the above phthalazines are potent inhibitors of SMOand the downstream transcription factors Gli1 and Gli2, and that exhibita desirable toxicology profile. In some embodiments, the inhibitor ofSMO, the inhibitor of Gli1, or the means for inhibiting Gli1 or SMO is acompound of Formula II:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof. Insome embodiments, the compound of Formula II isN-(1-(4,5-dimethyl-6-(1-methyl-1H-pyrazol-5-yl)pyridazin-3-yl)piperidin-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide,having the structure

also known as L-4.

L-4 is described in Zhu et al., (L-4, a Well-Tolerated and Orally ActiveInhibitor of Hedgehog Pathway, Exhibited Potent Anti-tumor EffectsAgainst Medulloblastoma in vitro and in vivo, Frontiers in Pharmacology10:89, 2019), which is hereby incorporated by reference in its entirety.Zhu et al. describe L-4 as a promising anti-cancer agent. It is reportedto have a similar ID₅₀ for Hh inhibition as taladegib, 2.33 nM versus2.26 nM, respectively.

Like taladegib and compounds of Formula I, L-4 and compounds of FormulaII constitute means for means for inhibiting Gli1 activity or means forinhibiting SMO. Various embodiments specifically exclude compounds ofFormula I, compounds of Formula II, or particular sub-genera or speciesof Formula I or Formula II.

The compounds of the present invention are capable of reaction, forexample, with a number of inorganic and organic acids to formpharmaceutically acceptable acid addition salts. Such pharmaceuticallyacceptable salts and common methodology for preparing them are wellknown in the art. See, e.g., P. Stahl, et al., HANDBOOK OFPHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH,2002); S. M. Berge, et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Sciences, Vol 66, No. 1, January 1977.

The herein disclosed compounds can be formulated as pharmaceuticalcompositions using a pharmaceutically acceptable carrier, diluent, orexcipient and administered by a variety of routes. In particularembodiments, such compositions are for oral or intravenousadministration. Such pharmaceutical compositions and processes forpreparing them are well known in the art. See, e.g., REMINGTON: THESCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al., eds., 19.sup.thed., Mack Publishing Co., 1995).

In some embodiments, the herein disclosed compounds of can be formulatedas tablets containing 50 or 100 mg of the compound and the commonpharmaceutical ingredients: croscarmellose sodium, HPMCAS-H, mannitol,microcrystalline cellulose, silicon dioxide, and sodium stearylfumarate. One particular embodiment contains 16.1% taladegib, 37.6%HPMCAS-H, 9.3% mannitol, 28.6% microcrystalline cellulose, 2.9%croscarmellose sodium, 1.0% silicon dioxide, 1.2% sodium stearylfumarate, and 3.4% Opadry (Film Coating).

IPF is a dysregulated wound healing process causing progressive fibroticlung scarring. Targeting the Hedgehog pathway is a logical therapeuticapproach to slow, halt or reverse progression of the disease. In woundhealing processes, the Hh pathway regulates the activation offibroblasts and transdifferentiation into myofibroblasts which whendysregulated become key drivers of fibrosis. In IPF myofibroblastsinfiltrate the lung where they produce extracellular matrix proteinssuch as collagen. The myofibroblasts adhere to the extracellular matrixand pull the lung closed similar to pulling a wound closed. The resultof the myofibroblast activity is progressive loss of lung functionthrough fibrosis and tissue remodeling.

Targeting the Hh pathway via Smo inhibition has been validated bothclinically and preclinically. In a clinical setting, the FDA-approvedSmo inhibitor, vismodegib (approved as Erivedge® for treatment of adultswith metastatic BCC or locally advanced BCC), was evaluated in a singlearm IPF study in combination with pirfenidone. After six months oftreatment, patients on average demonstrated an increase in Forced VitalCapacity (FVC) of approximately 100 mL. Increased FVC and lung capacityhave not been seen in previous clinical studies interrogating any othertarget considered for IPF. While Smo inhibition to disrupt the Hhpathway as a therapeutic target for IPF was validated, vismodegib waspoorly tolerated by patients, as severe muscle spasms were a significantadverse event resulting in discontinuation of over 40% of participants.This discontinuation rate is similar to the discontinuation rateexperienced by patients with BCC taking vismodegib. All furtherdevelopment for vismodegib as an IPF therapeutic was discontinued.

Inhibition of Gli1 mRNA in skin is similar to inhibition of Gli1 mRNA inthe lungs. Gli1 mRNA inhibition in skin biopsies has been measured as asurrogate for Gli1 mRNA inhibition in lungs in clinical studies of lungcancer. Nonclinical in vivo models demonstrated that the kinetics andmagnitude of Gli1 mRNA inhibition by orally administered taladegib werevery similar in the skin and lungs of mice. Additionally, the extent ofGli1 mRNA inhibition in the skin and lungs of mice was similar to theextent of Gli1 mRNA inhibition observed in the skin biopsies of humansubjects being treated with clinically relevant doses.

IPF patient samples have shown increased levels of Hh pathway componentsand myofibroblasts. Several studies examined tissues from IPF patientlung samples and compared them to lung samples of healthy subjects. Itwas clear there is a significant increase in SHh (the activating ligandof the Hh pathway) and Gli1. Normal lungs did not present with anydetectable amount of either SHh or Gli1, but IPF samples stained verystrongly indicating a significant presence. IPF lung samples alsostained very strongly for α-Smooth Muscle Actin 1 (α-SMA1) which is amarker that defines myofibroblasts. Normal healthy lung samples hadlittle to no staining of α-SMA1.

Hh pathway disruption to inhibit fibrosis has been demonstrated in vitroand in a number of animal models using several Smo inhibitors. Theseanimal models have similar features that capitulate fibroblastinfiltration and transdifferentiation into myofibroblasts that thendrive progressive fibrosis. Inhibition of Smo was observed to disruptfibrosis and in some cases reverse the disease. Additionally, it hasbeen demonstrated that inhibition of Smo resulted in increased apoptosisof infiltrated myofibroblasts, reduction of α-SMA1, reduction of Gli1and SHh, and reduction of collagen.

Nonclinical toxicity findings for taladegib are similar to approveddrugs in this class, with the important potential risks associated withon target effects of taladegib considered to be hepatic injury, effectson the reproductive organs, rhabdomyolysis, reproductive toxicity andbone effects. Class effects not yet observed with taladegib, clinicallyor nonclinically, include amenorrhea.

Clinically, the mean half-life (t_(½)) across all doses was estimated tobe approximately 16 hours for taladegib, allowing for once daily dosing.Median t_(max) was 2 hours.

Taladegib has demonstrated a favorable safety profile in 6industry-sponsored studies that have been conducted, primarily inadvanced cancer patients. As a monotherapy in advanced cancer, the mostcommonly observed adverse events (AEs) were nausea, diarrhea, dysgeusia,fatigue, decreased appetite, alopecia, vomiting, muscle spasm,constipation, weight decrease, and headache.

The relationship between the efficacy and toxicity of a drug isgenerally expressed in terms of therapeutic window and therapeuticindex. Therapeutic window is the dose range from the lowest dose thatexhibits a detectable therapeutic effect up to the maximum tolerateddose (MTD); the highest dose that will the desired therapeutic effectwithout producing unacceptable toxicity. Most typically therapeuticindex is calculated as the ratio of LD₅₀:ED₅₀ when based on animalstudies and TD₅₀:ED₅₀ when based on studies in humans (though thiscalculation could also be derived from animal studies and is sometimecalled the protective index), where LD50, TD₅₀, and ED₅₀ are the dosesthat are lethal, toxic, and effective in 50% of the tested population,respectively.

In various aspects of these embodiments the toxicity is an observabletoxicity, a substantial toxicity, a severe toxicity, or an acceptabletoxicity, or a dose-limiting toxicity (such as but not limited to aMTD). By an observable toxicity it is meant that while a change isobserved the effect is negligible or mild. By substantial toxicity it ismeant that there is a negative impact on the patient's overall health orquality of life. In some instances a substantial toxicity may bemitigated or resolved with other ongoing medical intervention. By asevere toxicity it is meant that the effect requires acute medicalintervention and/or dose reduction or suspension of treatment. Theacceptability of the toxicity will be influenced by the particulardisease being treated and its severity and the availability ofmitigating medical intervention.

Toxicities and adverse events are sometimes graded according to a 5point scale. A grade 1 or mild toxicity is asymptomatic or induces onlymild symptoms; may be characterized by clinical or diagnosticobservations only; and intervention is not indicated. A grade 2 ormoderate toxicity may impair activities of daily living (such aspreparing meals, shopping, managing money, using the telephone, etc.)but only minimal, local, or non-invasive interventions are indicated.Grade 3 toxicities are medically significant but not immediatelylife-threatening; hospitalization or prolongation of hospitalization isindicated; activities of daily living related to self-care (such asbathing, dressing and undressing, feeding oneself, using the toilet,taking medications, and not being bedridden) may be impaired. Grade 4toxicities are life-threatening and urgent intervention is indicated.Grade 5 toxicity produces an adverse event-related death. Thus, invarious embodiments, use of a drug in the herein disclosed regimen ordosage reduces the grade of a toxicity associated with treatment by atleast one grade as compared to use of that drug according to anotherregimen. In other embodiments, by use of a drug according to a specifiedregimen or dosage, a toxicity is confined to grade 2 or less, grade 1 orless, or produces no observation of the toxicity. In some embodiments, atherapeutic index of a herein disclosed inhibitor of Gli1 or SMO isgreater than that of vismodegib (approximately 0.37). In comparison, thetherapeutic of taladegib is approximately 8. In some embodiments, atherapeutic index of a herein disclosed inhibitor of Gli1 or SMO isgreater than 1, 2, 3, 4, 5, 6, or 7.

Aspects of the present specification provide, in part, administering aneffective amount (or therapeutically effective amount) of a compound ora composition disclosed herein. As used herein, the term “effectiveamount” is synonymous with “effective dose” and when used in referenceto treating IPF means at least the minimum dose of a compound orcomposition disclosed herein necessary to achieve the desiredtherapeutic effect. An effective dosage or amount of a compound or acomposition disclosed herein can readily be determined by the person ofordinary skill in the art considering all criteria (for example, therate of excretion of the compound or composition used, thepharmacodynamics of the compound or composition used, the nature of theother compounds to be included in the composition, the particular routeof administration, the particular characteristics, history and riskfactors of the individual, such as, e.g., age, weight, general healthand the like, the response of the individual to the treatment, or anycombination thereof) and utilizing his best judgment on the individual'sbehalf, especially in light of the exemplary dosages and otherinformation disclosed herein. In some embodiments, an effective dose is25, 50, 75, 100, 150, 200, 250, 300, 350, or 400 mg, or falls in a rangebound by any pair of the preceding values. In some embodiments, theeffective dose is administered once a day.

In some embodiments, the dosage of taladegib, L-4, or related compounds,is begun at 200 mg/day. In some embodiments, the dosage is provided in asingle daily dose. If grade 3 or higher AEs are observed, dosing isstepped down. In some embodiments, the dosage is stepped down indecrements of 50 mg/day as needed to avoid grade 3 or higher AEs, to aslittle as 50 mg/day. In some embodiments, an initial dosage (beforestep-down) can be any dosage higher than the lowest dosage deemed aneffective dose. In some embodiments, the initial dosage in is the tophalf of the effective dose range. In some embodiments, the initialdosage is at the top of the effective dose range. For example, if theeffective dose range in 50-200 mg, an initial dose could be >50 mg(e.g., 75 mg), 125-200 mg, or 200 mg. In some instances, the initialdosage is in a range of 100-300 mg/day. In some instances, the step-downin dosage is 25, 50, or 100 mg/day.

In some embodiments, an effective dose of the inhibitor of Gli1 or SMO,or means for inhibiting Gli1 or SMO results in stabilization orimprovement of fibrosis, such as with respect to the physical extent offibrosis, lung function, or other measure as described herein. Infurther embodiments, the stabilization or improvement of fibrosis isachieved without the patient experiencing drug-related adverse events(toxicities). In particular instances, the avoided drug-related adverseevents are grade 3 or higher toxicities. In some embodiments, the absentdrug-related adverse events are muscle spasms, QT elongation or a livertoxicity.

Various aspects are methods of treating fibrosis by administering aninhibitor of Gli1 or SMO, or means for inhibiting Gli1 or SMO, to apatient in need thereof, that is, a patient having a fibrotic disease.In some embodiments, the inhibitor of Gli1 or SMO, or means forinhibiting Gli1 or SMO is used as monotherapy. In some embodiments, theinhibitor of Gli1 or SMO, or means for inhibiting Gli1 or SMO is used incombination with another anti-fibrosis drug. In some embodiments, theother anti-fibrosis drug is not a Hh pathway inhibitor. In some instancethe non-Hh pathway inhibitor anti-fibrosis drug is pirfenidone,nintedanib, GLPG4716 or PRM-151.

In some embodiments, the fibrotic disease is idiopathic pulmonaryfibrosis (IPF). In some embodiments, the fibrotic disease is pulmonaryfibrosis following infection, including a bacterial or viral infection.In most instances, the fibrosis develops after years-long chronicinfections so that the role of the infection in causing the fibrosiscannot be conclusively demonstrated; such fibrosis is therefore stillclassified as idiopathic. Covid-19 provides a counterpoint, in thatonset of fibrosis can be very rapid. In some embodiments, the pulmonaryfibrosis follows infection with SARS-CoV-2. In some embodiments, thefibrotic disease is scleroderma. In some instances, the fibrotic diseaseis systemic scleroderma (also known as systemic sclerosis) and infurther instances, systemic scleroderma involving the lung. In someembodiments, the fibrotic disease is liver fibrosis, such as innon-alcoholic steatohepatitis (NASH). In some embodiments, the fibroticdisease is kidney fibrosis, for example, renal interstitial fibrosis orrenal allograft fibrosis. In some embodiments, the fibrotic disease isgastric fibrosis, for example, gastric mucosal fibrosis, glandularstomach fibrosis, or retroperitoneal fibrosis. In some embodiments, thepatient is a human. In some embodiments, the patient is a non-humananimal, for example a mammal.

For each method of treatment, there are parallel embodiments expressedas use of the inhibitor of Gli1 or SMO, or the means for inhibiting Gli1or SMO, in the treatment of a fibrotic disease, or their use in themanufacture of a medicament for the treatment of a fibrotic disease, ora composition or pharmaceutical composition for use in treating afibrotic disease, and the like.

The terms “treatment” “treating”, etc., refer to the medical managementof a patient with the intent to cure, ameliorate, stabilize, or preventa disease, pathological condition, or disorder. This term includesactive treatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. Various embodiments may specifically include orexclude one or more of these modes of treatment.

Treatment activity includes the administration of the medicaments,dosage forms, and pharmaceutical compositions described herein to apatient, especially according to the various methods of treatmentdisclosed herein, whether by a healthcare professional, the patienthis/herself, or any other person. Treatment activities include theorders, instructions, and advice of healthcare professionals such asphysicians, physician's assistants, nurse practitioners, and the like,that are then acted upon by any other person including other healthcareprofessionals or the patient him/herself. This includes, for example,direction to the patient to undergo, or to a clinical laboratory toperform, a diagnostic procedure, such as imaging or an evaluation oflung function, so that ultimately the patient may receive the benefitappropriate treatment. In some embodiments, the orders, instructions,and advice aspect of treatment activity can also include encouraging,inducing, or mandating that a particular medicament, or combinationthereof, be chosen for treatment of a condition—and the medicament isactually used—by approving insurance coverage for the medicament,denying coverage for an alternative medicament, including the medicamenton, or excluding an alternative medicament, from a drug formulary, oroffering a financial incentive to use the medicament, as might be doneby an insurance company or a pharmacy benefits management company, andthe like. In some embodiments, treatment activity can also includeencouraging, inducing, or mandating that a particular medicament bechosen for treatment of a condition—and the medicament is actuallyused—by a policy or practice standard as might be established by ahospital, clinic, health maintenance organization, medical practice orphysicians group, and the like. All such orders, instructions, andadvice are to be seen as conditioning receipt of the benefit of thetreatment on compliance with the instruction. In some instances, afinancial benefit is also received by the patient for compliance withsuch orders, instructions, or advice. In some instances, a financialbenefit is also received by the healthcare professional for compliancewith such orders, instructions, or advice.

Treatment efficacy or benefit for pulmonary fibrosis is commonlyassessed by changes in lung function for example, as determined byspirometry. Spirometry measures that can be used include forced vitalcapacity (FVC), forced expiratory volume in 1 second (FEV₁), anddiffusion capacity of the lungs for carbon monoxide (DL_(CO)). Furtherspirometry parameters that can be considered include FEV₁/FVC ratio,observed FVC as a percentage of predicted FVC (FVC % predicted), andobserved FEV₁ as a percentage of predicted FEV₁ (FEV₁% predicted). Thepredicted value of FVC (in liters) as published by the Association forRespiratory Technology and Physiology is 5.76*height (inmeters)−0.026*age (in years)−4.34. The predicted value of FEV₁ (inliters) as published by the Association for Respiratory Technology andPhysiology is 4.30*height (in meters)−0.029*age (in years)−2.49.

Other assessments include:

-   -   appearance of the lungs—quantitative extent of fibrosis        (including scarring or remodeling), by percent and/or volume, as        determined by CT scan, magnetic resonance imaging (MRI), and the        like;    -   appearance of the lungs—qualitative extent of fibrosis:        improved, same, or worse), as determined by CT scan, magnetic        resonance imaging (MRI), and the like;    -   the number of respiratory hospitalizations;    -   the distance that can be walked in a set interval of time, for        example, 6-minute walk distance; and    -   scores on a respiratory health questionnaire, for example, St.        George's Respiratory Questionnaire, the UCSD Shortness of Breath        Questionnaire, and the like. Assessments.

The spirometry and other assessments may be made at regular intervals,for example, about every 24 weeks, quarterly, semi-annually, orannually.

Treatment efficacy or benefit may be observed as a decrease in theprogression of the disease, a stabilization of the disease, orimprovement in the patient's condition. In some embodiments,progression, stabilization, or improvement is judged in comparison to aprevious measurement or measurements of that patient. In someembodiments, the previous measurement is a baseline measurement prior toinitiation of treatment. In some embodiments, progression,stabilization, or improvement is judged based in comparison with otherpatients, actual or historical, receiving no treatment, placebo, oralternative treatment. Thus, in some embodiments, improvement orstabilization is judged by comparison to what would be expected in anuntreated patient. For example, in such embodiments, decreased scarringincludes an increase in scarring that is less than would be expected inan untreated patient. Thus a stabilization of lung function does notimply no further decrease in one or another measure of lung function butrather that any decrease does not exceed that expected with aging forthe time interval considered.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification,

Example 1 In Vitro Pharmacology of Taladegib

Using an in vitro competitive binding assay, half-maximal inhibitoryconcentration (IC₅₀) and binding constant (K_(i)) were calculated basedon the competitive displacement of a radioligand. Taladegib binds tohSMO receptor and inhibits binding of ³H-2406189 (a known hSMO agonist)to hSMO, with K_(i) of 76.4±75.3 nM and IC₅₀ of 144±143 nM (n=4,geometric mean±standard error [SE]).

To determine the biological activity of taladegib in mouse cells,Gli-Luciferase activity was quantified in a mouse mesenchymal C3H10T½cell line stimulated with sonic hedgehog conditioned media (SHh-CM).Taladegib hydrochloride inhibited Hh signaling activity in mouse C3H10T½cells with an IC₅₀ of 11.2±5.33 nM (n=8, geometric mean±SE). Todetermine the biological activity of taladegib in human cells, Gli1transcript levels were quantified in a human Daoy tumor cell linestimulated with SHh-CM. Taladegib hydrochloride inhibited Hh signalingactivity in human Daoy cells with an IC₅₀ of 2.22±1.14 nM as determinedby measurement of Gli1 mRNA using branched chain deoxyribonucleic acid(DNA) assay technology (n=8, geometric mean±SE).

Example 2 In Vivo Pharmacology of Taladegib

In order to understand PK/PD effects and to guide the dosing regimen forefficacy studies, key PK/PD studies involving dose response and timecourse were carried out following a single oral administration of thetaladegib in Balb/c surrogate and PTCH^(−/+)×p53^(−/−) tumor models.Following the predetermined dosing period, surrogate tissues (lung,skin, and cerebellum) from Balb/C mouse and tumor fromPtch^(−/+)×p53^(−/−) transgenic tumor model were harvested, processed,and evaluated for Gli1 expression levels using a quantitative reversetranscription polymerase chain reaction TaqMan® assay. As summarized inTable 1, taladegib inhibited Hh signaling as measured by mouse Gli1expression levels in tissues evaluated. The time course studydemonstrated that sustained target inhibition can be maintained for atleast 24 hours following a single oral dose of taladegib hydrochlorideat 8 mg/kg. Given the parallel PD effects, skin Gli1 is an appropriatePD surrogate for lung tissue Gli1.

TABLE 1 Summary Table of TED₅₀ and TEC₅₀ of Taladegib Hydrochloride inMouse Pharmacodynamic Models Lung mGli1 Skin mGli1 Cerebellum mGli1Brain Tumor mGli1 TED₅₀ TEC₅₀ TED₅₀ TEC₅₀ TED₅₀ TEC₅₀ TED₅₀ TEC50 Mouse(mg/kg) (ng/mL) (mg/kg) (ng/mL) (mg/kg) (ng/mL) (mg/kg) (ng/mL) Balb/c2.6 ± 0.6 264 ± 114 1.1 84 2.2 230 — — PTCH Tg — — — — — — 1.0 63.0Abbreviations: SE = standard error; TEC50 = threshold effectiveconcentration; TED50 = threshold effective dose; Tg = transgenic.

Example 3 SMO Inhibitor Improves FVC in IPF Patients

The results of various clinical trials of treatments for IPF werecompared (FIG. 1). Whereas the anti-inflammatory pirfenidone, and thekinase inhibitor nintedanib, were only able to slow the deterioration ofFVC, the SMO inhibitor vismodegib (in combination with pirfenidone) wasable to produce a substantial increase in FVC, suggesting a reversal ofpathology. The autotaxin inhibitor zirtaxestat (also known as GLPG1690)produced a small increase in FVC in a Phase 1 b trial, howeverdevelopment of this drug was abandoned during a phase 3 trial due to arisk-benefit profile that in the assessment of an Independent DataMonitoring Committee no longer supported its use. All development ofziraxestat has been discontinued. Development of vismodegib was alsodiscontinued for IPF treatment due to severe muscle spasms, but thesedata validate the use of Hh inhibitors in the treatment of IPF.

Example 4 Lower Doses of Taladedib Reduce Severity of Muscle SpasmAdverse Events but Maintain Decree of Glil Inhibition

Taldegib was administered to subjects at doses of 50, 100, 200, 400 and600 mg. At these doses most patients exhibited >80% inhibition of Gli asmeasured in skin biopsies (FIG. 2). While some grade 3 toxicities wereseen at 400 mg/day, there were none at 200 or 100 mg/day (Table 2).Given that the minimal biological effective dose (BED) was defined inthis study as the first dose level at which the inhibition of mGli1was >50%, it was concluded that taladegib was pharmacologically activeat all dose levels tested.

TABLE 2 Dose - Muscle Spasm AE Correlation Muscle Spasm Adverse EventFrequency Reported Dose level Grade 1 Grade 2 Grade 3 Grade 4 (n pa- (npa- (n pa- (n pa- (n pa- tients) tients) tients) tients) tients) 100 mg(24)^(T) 21% (5) 0 0 0 200 mg (12) ^(T) 17% (2) 17% (2) 0 0 400 mg (90)^(T) 17% (15) 10% (9) 4% (4) 0 150 (104) ^(V) 43% (45) 22% (23) 6% (7) 0AE data collected from multiple clinical trials including a phase 1btrial for combination with etoposide and carboplatin. Dose levels withless than 10 patients excluded due to insufficient power. ^(T) taladegib^(V) vismodegib

Example 5 Comparison of Predominant AEs for Drugs Tested for IPFTreatment

Taladegib, vismodegib, pirfenidone, and nintedanib have all been used inclinical trials and have been used or evaluated for use in treating IPF.Except for taladegib, >20% of patients discontinued treatment for drugrelated reasons (FIG. 3). The predominant AE causing discontinuation wasmuscle spasms for vismodegib, nausea for pirfenodone, and diarrhea fornintedanib. There was no prevalent AE for taladegib and <10% patientsdiscontinued treatment for drug related reasons when the dosage was ≤200mg/day.

Example 6 Reduction of Myofibroblasts in Bleomycin-Induced PulmonaryFibrosis Model

The Bleomycin (BLM) induced pulmonary fibrosis model is a standard IPFmodel, widely used in pharmacology and fundamental research. The diseaseIPF is defined as injury confined to the lungs that is progressive andirreversible. In IPF patients, loss of lung function is driven by theinfiltration and expansion of activated myofibroblasts. A Microsprayer®Aerosolizer was used to perform intratracheal administration ofbleomycin. By administering bleomycin via Microsprayer® Aerosolizer, itcan be evenly exposed to the lungs and thus, develops a reproducible anduniform pathology. In this model, the presence of myofibroblasts areobserved by immunohistochemistry when stained with anti-alpha-smoothmuscle actin (α-SMA) antibodies.

Animals were exposed to bleomycin and then treated with taladegib at theonset of fibrosis on day seven. Pathology of animals was examined on day21 of the study. Treatment with taladegib at 5 mg/kg orally administereddaily resulted in approximately 40% reduction of α-SMA proteinexpression indicating a reduction of myofibroblasts (FIGS. 4A-B).

Example 7 A Phase 2, Multi-Center Study Evaluating the Safety andEfficacy of Taladegib in Subjects with IPF

Patients diagnosed with IPF based upon American Thoracic Association,Japanese Respiratory Society, European Respiratory Society, LatinAmerican Thoracic Association guidelines, and confirmed by highresolution computed tomography (HRCT), having percent predicted FVCof >50% and percent predicted DLCO between 35% and 85%, are randomizedin to taladegib and placebo groups. Baseline results from lung functiontests (FVC, FEV₁ and DL_(CO)), HRCT, and the UCSD Shortness of Breath(SOB) questionnaire are obtained. Taladegib is administered daily for 12weeks, starting at 200 mg/day. The patients are observed an additional 6weeks after the scheduled treatment is completed. If medication-relatedadverse events are experienced, the dosage may be reduced to as littleas 100 mg/day. Lung function tests and the UCSD SOB questionnaire areadministered again at weeks 6, 12, and 18 of the study. HRCT is repeatedat 12 weeks. Efficacy is assessed by change from baseline for FVC, FEV₁,FEV₁/FVC ratio, FVC % predicted, FEV₁ % predicted, and DL_(CO) and theUCSD SOB questionnaire at weeks 6, 12, and 18. Quantitative (% and mL)and qualitative (improved, same, worse) assessment of lung fibrosis byHRCT will be performed at Screening and Week 12. The Screening HRCT willserve as the baseline for study HRCT assessments. At 12 weeks, no orlimited dose limiting toxicities are observed. At 12 weeks, someefficacy endpoints demonstrate stabilization or improvement. At 18weeks, durability of the response is observed. Patients did notexperience serious drug-related adverse events (after sufficientstep-down of dosage, if any), including the absence of muscle spams.

Example 8 Covid-19 Therapy Clinical Trial

Patients recovered from SARS-CoV-2 infection showing lung fibrosis by CTscan are randomized for treatment with standard of care or taladegibmonotherapy. Taladegib is administered daily starting at 200 mg. Ifmedication-related adverse events are experienced, the dosage may bereduced in steps of 100 mg to reduce or eliminate adverse events.Phamacokinetic data is collected. The primary efficacy endpoint is FVCchange from baseline at 24 weeks. Secondary efficacy endpoints arechange in lung fibrosis from baseline CT scan, change from baseline in6-minute walk distance, the number of adjudicated respiratoryhospitalizations, and change from baseline in St. George's RespiratoryQuestionnaire. At 24 weeks some efficacy endpoints demonstratestabilization or improvement. Patients did not experience seriousdrug-related adverse events (after sufficient step-down of dosage, ifany), including the absence of muscle spams.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

1. A method of treating fibrosis comprising administering moans forinhibiting a Gli1 inhibitor to a patient in need thereof.
 2. The methodof claim 1, wherein said Gli1 inhibitor comprises a compound of FormulaI:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof. 3.The method of claim 2, wherein R¹ is methyl, R² is methyl, R³ istrifluoromethyl, R⁴ is H, R⁵ is fluoro, R⁶ is H.
 4. The method of claim1, wherein said Gli1 inhibitor comprises a compound of Formula II:

wherein, R¹ is hydrogen or methyl; R² is hydrogen or methyl; R³, R⁴, R⁵,R⁶, or R⁷ are independently hydrogen, fluoro, chloro, cyano,trifluoromethyl, trifluoromethoxy, difluoromethoxy, methylsulfonyl, ortrifluoromethylsulfonyl, provided that at least three of R³, R⁴, R⁵, R⁶,and R⁷ are hydrogen; or a pharmaceutically acceptable salt thereof. 5.The method of claim 4, wherein said Gli1 inhibitor comprises L-4.
 6. Themethod of claim 1, comprising administering 50-200 mg of said means orcompound.
 7. The method of claim 6, wherein an initial dosage of 100-300mg is administered but upon the patient experiencing a drug-relatedadverse event, the dosage is stepped down.
 8. The method of claim 1,wherein the fibrosis is idiopathic pulmonary fibrosis.
 9. The method ofclaim 1, wherein the fibrosis is systemic scleroderma.
 10. The method ofclaim 1, wherein the fibrosis is pulmonary fibrosis following apulmonary infection.
 11. The method of claim 10, wherein the pulmonaryinfection was infection by SARS-CoV-2.
 12. The method of claim 1,wherein toxicity is confined to grade 2 or less.
 13. The method of claim1, wherein fibrosis does not progress after initiation of treatment. 14.The method of claim 1, wherein the fibrosis is a pulmonary fibrosis andlung function is stabilized.
 15. The method of claim 1, wherein thefibrosis is a pulmonary fibrosis and lung function is improved.
 16. Themethod of claim 1, wherein the fibrosis is a pulmonary fibrosis andscarring is decreased.
 17. The method of claim 1, wherein lung functionis assessed by a parameter selected from the group consisting of forcedvital capacity (FVC), forced expiratory volume in 1 second (FEV1),diffusion capacity of the lungs for carbon monoxide (DL_(CO)), FEV1/FVCratio, FVC % predicted, FEV1% predicted, a quantitative assessment ofthe extent of fibrosis from imaging of the lungs, a qualitativeassessment of the extent of fibrosis from imaging of the lungs, thenumber of respiratory hospitalizations, the distance that can be walkedin a set interval of time; and scores on a respiratory healthquestionnaire.